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Description
標的DNAの配列決定を行うための新規アプローチを以下に提示する。本方法は、標的DNA捕捉デバイスとしての役割を果たすように、固相支持体上で汎用プライマー叢(lawn)(すなわち、ランダムに分布された少なくとも2つのプライマーを含有する叢)を修飾し、サンプルを大幅に操作することなく、捕捉されたDNAの直接的な配列決定を可能にすることに基づく。本方法は、関連する流体プラットフォームを用いて、標的DNAの捕捉と配列決定実験のシームレスな統合を可能にする。このアプローチは、その配列決定の可能性を維持しながら、固相支持体上でDNA捕捉基質としての役割を果たす普遍的プライマー叢を使用する。本方法は、配列決定のための鋳型として未処理の天然DNAを使用することができる。この方法を使用した配列決定は、必ずしも研究施設に依存するわけではない。さらに、サンプル処理の間に導入されるあらゆるバイアスが回避され、他の方法と比較してより少ない時間および低コストで実質的により小さなサンプルを分析することができる。本方法は、一本鎖および二本鎖の鋳型を分析するために使用することができる。一本鎖DNA鋳型を分析する能力は、病理学アーカイブからのホルマリン固定パラフィン包埋サンプルを使用するいくつかの配列決定用途にとって重要であり得る。同様に、一本鎖DNA鋳型による配列決定を可能にすることにより、本方法は、複雑な核酸抽出ステップ、およびDNAの二本鎖編成を保存するように設計された高価な断片化機器を必要としない。むしろ、廉価かつ効率的な溶解および加熱による断片化によってサンプルを調製することができる。単純な捕捉・配列決定アッセイは、ヒトゲノムDNAに限定されず、細菌およびウイルスのDNAおよびRNA等の他の核酸基質も分析することができる。トランスクリプトーム、非翻訳領域、およびmiRNAも、捕捉および配列決定することができる。また、ヌクレオチド配列の捕捉および配列決定、他の遺伝子特性およびエピジェネティックな特性(DNAメチル化、大きなゲノムの再編成、および遺伝子発現等)も調べることができる。本方法は、集団から合成DNAを選択するためにも用いることができる。 A novel approach for sequencing target DNA is presented below. The method modifies a universal primer lawn (ie a plex containing at least two randomly distributed primers ) on a solid support to serve as a target DNA capture device and Based on allowing direct sequencing of the captured DNA without significant manipulation. The method allows for seamless integration of target DNA capture and sequencing experiments using an associated fluid platform. This approach uses a universal primer plexus that serves as a DNA capture substrate on the solid support while maintaining its sequencing possibilities. The method can use unprocessed natural DNA as a template for sequencing. Sequencing using this method is not necessarily laboratory dependent. In addition, any bias introduced during sample processing is avoided, and substantially smaller samples can be analyzed in less time and cost compared to other methods. The method can be used to analyze single and double stranded templates. The ability to analyze single-stranded DNA templates can be important for some sequencing applications using formalin-fixed paraffin-embedded samples from pathology archives. Similarly, by allowing sequencing with single-stranded DNA templates, the method requires complex nucleic acid extraction steps and expensive fragmentation equipment designed to preserve the double-stranded organization of the DNA. And not. Rather, the sample can be prepared by inexpensive and efficient lysis and fragmentation by heating. Simple capture and sequencing assays are not limited to human genomic DNA, but can also analyze other nucleic acid substrates such as bacterial and viral DNA and RNA. Transcriptomes, untranslated regions, and miRNAs can also be captured and sequenced. Nucleotide sequence capture and sequencing, other genetic and epigenetic properties (such as DNA methylation, large genome rearrangements, and gene expression) can also be examined. The method can also be used to select synthetic DNA from a population.
一般的に、配列決定は、DNAサンプルが、配列決定システム上での分析を促進するように構造的に修飾されるプロセスとして見なされてきた。以下に記載する方法は、配列決定システムを修飾するため、サンプルを修飾して大規模に調製する必要がない。合成DNAを使用して汎用プライマー叢を官能基化することにより、未処理サンプルの標的遺伝子のオリゴヌクレオチドライブラリーを直接的にアッセイすることができる。非特異的捕捉を減少させるために、ブリッジ構造の形成において用いられる配列を提供する特異的DNA構成要素を経時的に導入すると、プライマー叢自体が修飾される。あらゆる種類のシーケンサーのための配列決定用ライブラリーの調製は、特異的二本鎖アダプター配列をDNA鋳型に付加することに依存する。捕捉オリゴヌクレオチドが固体支持体上に固定化されたアダプターとしての役割を果たしたため、アッセイのためのライブラリーの調製は、単一アダプターの付加を必要とするだけであった。これによって、サンプル処理が実質的に短縮され、クローン増幅またはゲル電気泳動に基づくサイズ分別が不要となる。特定の場合において、固体支持体上で捕捉された鋳型に第2のアダプターが付加されてもよい。本方法の特定の実施形態は、配列決定用の鋳型としての粗DNAの使用を可能にする。 In general, sequencing has been viewed as a process in which a DNA sample is structurally modified to facilitate analysis on a sequencing system. The methods described below modify the sequencing system so that the sample need not be modified and prepared on a large scale. By functionalizing the universal primer suite using synthetic DNA, an oligonucleotide library of target genes in the untreated sample can be directly assayed. In order to reduce non-specific capture, the primer plexus itself is modified when specific DNA components are introduced over time that provide the sequence used in the formation of the bridge structure. The preparation of a sequencing library for any kind of sequencer relies on the addition of specific double stranded adapter sequences to the DNA template. Since the capture oligonucleotide served as an adapter immobilized on the solid support, preparation of the library for the assay required only the addition of a single adapter. This substantially shortens sample processing and eliminates the need for size fractionation based on clonal amplification or gel electrophoresis. In certain cases, a second adapter may be added to the template captured on the solid support. Certain embodiments of the method allow the use of crude DNA as a template for sequencing.
追加の実施形態は、断片化DNAを鋳型として使用すること、および流体システムを使用して、捕捉されたDNA断片に配列決定アダプターを付加することにより、固体支持体上での配列決定のためにDNA断片の調製を可能にする方法を提供する。概念実証として、Illumina社の次世代DNAシーケンサーを使用してこれらのアプローチを開発した。プライマー叢の修飾およびヒトゲノム中の366ヶ所の標的部位を使用した、統合された捕捉および配列決定調製反応の結果を提示する。25分間の加熱による断片化を除いて、全てのステップをIllumina社のフローセルの固相支持体上で行うことができる。 Additional embodiments provide for sequencing on a solid support by using fragmented DNA as a template and adding a sequencing adapter to the captured DNA fragment using a fluid system. Methods are provided that allow the preparation of DNA fragments. As a proof of concept, these approaches were developed using Illumina's next generation DNA sequencer. Presents the results of integrated capture and sequencing preparation reactions using primer plex modifications and 366 target sites in the human genome. With the exception of fragmentation by heating for 25 minutes, all steps can be performed on the solid support of an Illumina flow cell.
以下に記載するデータは、アッセイのロバスト性、ならびに捕捉基質としての普遍的プライマー叢および流体システムの適用性を証明するものである。本方法がロバストに作用することを可能にする、プライマー叢の修飾の特有のパラメータを同定した。複雑な真核生物のゲノムに加えて、本方法は、真菌および他の微生物のゲノム、ウイルスのDNAおよびRNA、異なる源のトランスクリプトーム、ならびに合成DNAを捕捉するためにも適用できる。さらに、流体システムの固体支持体上に固定化された未変性のプライマー叢を「プログラミング」して、特異的な用途を実行するという概念を導入して立証した。 The data set forth below demonstrates the robustness of the assay and the applicability of universal primer plexus and fluid systems as capture substrates. We identified a unique parameter of primer plex modification that allows the method to work robustly. In addition to complex eukaryotic genomes, the method can also be applied to capture fungal and other microbial genomes, viral DNA and RNA, transcriptomes of different sources, and synthetic DNA. Furthermore, the concept of “programming” the native primer plexes immobilized on the solid support of the fluid system was introduced and proved to perform a specific application.
標的選択およびコンピュータによるOS−Seqオリゴヌクレオチドの設計 CCDS Build Release 20090902、NCBIのヒトゲノムBuild37−hg19、およびdbSNP Build ID131を多型参照データセットとして使用した。遺伝子選択のために、GeneRankerアノテーションデータベースを使用して、重要性によって優先順位をつけた344個の癌遺伝子を選択した。オリゴヌクレオチドの標的特異的配列を検索するために、候補遺伝子のためのエクソンの定義をCCDSから採択した。標的エクソン(500bp未満)のほとんどにおいて、40−mer標的特異的配列が、エクソン境界の5’末端の10塩基外側にあった(図3a)。個々のプライマー・プローブを使用してエクソンの両方の鎖を標的とした。OS−Seq−366は、エクソンの隣接領域のみを覆っていた。OS−Seq−11kアッセイにおいて、エクソン領域全体が覆われるまで標的特異的配列をタイリングすることにより、500bpよりも大きいエクソンを処理した(図3b)。OS−Seq−11kのオンターゲット特異性を向上させるために、Repbaseを使用して反復性の高い配列を標的とするオリゴヌクレオチド配列を同定し、排除した。 Target selection and computational OS-Seq oligonucleotide design CCDS Build Release 2009902, NCBI human genome Build37 - hg19, and dbSNP Build ID131 were used as polymorphic reference data sets. For gene selection, the GeneRanker annotation database was used to select 344 oncogenes prioritized by importance. In order to search for target-specific sequences of oligonucleotides, exon definitions for candidate genes were adopted from CCDS. In most of the target exons (less than 500 bp), the 40-mer target specific sequence was 10 bases outside the 5 ′ end of the exon boundary (FIG. 3a). Individual primers and probes were used to target both strands of exons. OS-Seq-366 only covered the adjacent region of the exon. In the OS-Seq-11k assay, exons larger than 500 bp were processed by tiling target specific sequences until the entire exon region was covered (FIG. 3b). In order to improve the on-target specificity of OS-Seq-11k, Repbase was used to identify and eliminate oligonucleotide sequences targeting highly repetitive sequences.
フローセルプライマー叢の修飾によるOS−Seqプライマー・プローブの合成 Illumina社のGenome Analyzer IIx(Illumina、San Diego)システムにおいて、固相支持体(すなわち、フローセル)は、ポリアクリルアミド層上に極めて高密度でランダムに固定化された2つのプライマー(「C」および「D」)を有する。OS−Seq実験のために、Illumina社のCluster Stationを使用して「D」プライマーのサブセットを特異的に修飾した。NGSプライマー修飾の前に、133nMオリゴヌクレオチドのプールを95℃で5分間熱変性させた。熱ショック(95℃で5分間)を用いてOS−Seqオリゴヌクレオチドのコード鎖を遊離させた。第2の鎖はフローセル上で不活性であり、ハイブリダイゼーション後に洗浄されたため、さらなる鎖の精製は必要なかった。変性オリゴヌクレオチドを4xハイブリダイゼーションバッファー(20xSSC、0.2%Tween−20)で希釈した。得られた100nMオリゴヌクレオチドをフローセル修飾実験に使用した。30μlのオリゴヌクレオチド混合物をフローセルの各レーンに分注した。温度勾配(18分間で96℃から40℃)の間に、オリゴヌクレオチドは、固定化プライマー「D」に特異的にアニールした。次いで、アニールしたオリゴヌクレオチドを鋳型として「D」プライマーを伸長させるためにDNAポリメラーゼを使用した。伸長後、元のオリゴヌクレオチド鋳型を伸長させた「D」プライマーから変性させ、固相支持体から洗浄した。伸長、洗浄、および変性ステップには標準的なIllumina社のv4試薬を使用した。プライマー「D」の修飾によって、プライマー・プローブの固定化がもたらされた。 Flow cell primer modification by the synthesis Illumina's OS-Seq primer-probes flora Genome Analyzer IIx (Illumina, San Diego) in the system, the solid support (i.e., flow cell) is a very high density on the polyacrylamide layer random It has two primers ("C" and "D") immobilized on it. For OS-Seq experiments, Illumina Cluster Station was used to specifically modify a subset of “D” primers. Prior to NGS primer modification, the pool of 133 nM oligonucleotides was heat denatured at 95 ° C. for 5 minutes. The heat-shock (95 ° C. for 5 minutes) was used to release the OS-Seq oligonucleotide coding strand. Since the second strand was inactive on the flow cell and was washed after hybridization, no further strand purification was required. Denatured oligonucleotides were diluted with 4 × hybridization buffer (20 × SSC, 0.2% Tween-20). The resulting 100 nM oligonucleotide was used for flow cell modification experiments. 30 μl of the oligonucleotide mixture was dispensed into each lane of the flow cell. During the temperature gradient (96 ° C. to 40 ° C. over 18 minutes), the oligonucleotides specifically annealed to the immobilized primer “D”. DNA polymerase was then used to extend the “D” primer using the annealed oligonucleotide as a template. After extension, the original oligonucleotide template was denatured from the extended “D” primer and washed from the solid support. Standard Illumina v4 reagents were used for the extension, wash, and denaturation steps. Modification of primer “D” resulted in immobilization of the primer probe.
OS−Seqの処理は3つのステップを伴う:Illumina社の配列決定システムを、標的特異的プライマー・プローブを含むように修飾し、単一アダプターライブラリーから標的を捕捉し、固定化された断片を配列決定のために完成させる(図1b)。捕捉基質を調製するために、既存のプライマー叢のサブセットを標的特異的プライマー・プローブになるように修飾することにより、Illumina社のフローセルを分子的に再設計する。これらのプライマー・プローブを作製するために、オリゴヌクレオチドの複雑なプールの3’普遍的配列をフローセル上でその補体とハイブリダイズさせ、DNAポリメラーゼ伸長反応を使用して固定化プライマーを伸長させる。ランダムに配置された標的特異的プライマー・プローブのセットが得られ、フローセル表面上に固定される。65℃の高温インキュベーションの間に、プライマー・プローブは、単一アダプターゲノムDNAライブラリー内の標的相補的配列に特異的にハイブリダイズする:ハイブリダイゼーション後、次いで、プライマー・プローブは、別のDNAポリメラーゼ伸長反応のためのプライマーとして機能する。伸長ステップは、標的配列を効率的に捕捉する。伸長後、変性ステップを行い、次いで、40℃の低温ハイブリダイゼーションにより配列決定用ライブラリーアダプターをフローセル上でその補体に安定化させ、ブリッジ構造を作製する。第3のDNAポリメラーゼ伸長反応により、3’末端に追加の配列を組み込み、固相増幅が可能な2つの分子を作製する。OS−Seqに特異的な3つのステップの後、捕捉された分子をブリッジ増幅し、処理し、Illumina社のNGSシステムからの標準的な配列決定プロトコルを使用して配列決定する。OS−Seqにおける分子生物学的ステップの詳細な説明は、上記に示され、Illumina社のOS−Seq用Cluster Stationプログラムはそれに応じて変更される。 The OS-Seq process involves three steps: the Illumina sequencing system is modified to include target-specific primer probes to capture the target from a single adapter library, and the immobilized fragment is Complete for sequencing (Figure 1b). To prepare the capture substrate, the Illumina flow cell is molecularly redesigned by modifying a subset of the existing primer plexes to be target-specific primer probes. To make these primer probes, the 3 'universal sequence of a complex pool of oligonucleotides is hybridized with its complement on a flow cell and the immobilized primer is extended using a DNA polymerase extension reaction. A randomly placed set of target-specific primers and probes is obtained and immobilized on the flow cell surface. During a high temperature incubation at 65 ° C., the primer probe specifically hybridizes to the target complementary sequence in the single adapter genomic DNA library: After hybridization, the primer probe then becomes another DNA polymerase. Functions as a primer for the extension reaction. The extension step efficiently captures the target sequence. After extension, a denaturation step is performed, and then the library adapter for sequencing is stabilized to its complement on the flow cell by low-temperature hybridization at 40 ° C. to produce a bridge structure. A third DNA polymerase extension reaction incorporates an additional sequence at the 3 ′ end to produce two molecules capable of solid phase amplification. After three steps specific for OS-Seq, the captured molecules are bridge amplified, processed, and sequenced using a standard sequencing protocol from the Illumina NGS system. A detailed description of the molecular biological steps in OS-Seq is given above, and Illumina's Cluster Station program for OS-Seq will be modified accordingly.
原理の実証の証拠として、2つの捕捉アッセイを開発した。最初に、10個の癌遺伝子のエクソンに隣接する366個のOS−Seqプライマー・プローブ(OS−Seq−366)を設計した(図3)。このアッセイは、OS−Seqの方法をテストすることを企図するものであって、決定的なエクソンカバレッジをテストすることを企図するものではなかった。カラムに基づく方法を使用してOS−Seq−366オリゴヌクレオチドを合成した。次に、拡張性を証明するために、344個の癌遺伝子のエクソンを捕捉するための11,742個のプライマー・プローブを設計および合成した(OS−Seq−11k)。これらのプライマー・プローブは、エクソンカバレッジの向上のために、反復を避けて大きなエクソンにわたってタイリングした。OS−Seq−11kのハイスループットな産生のために、プログラム可能なマイクロアレイ上でオリゴヌクレオチドを合成した。これらのアレイ合成オリゴヌクレオチドは、処理のためおよびOS−Seqに十分な材料を得るために増幅を必要とする(図4)。処理後、OS−Seqオリゴヌクレオチドは、標的領域の5’末端に相補的な標的特異的40−merを含有する(図5)。また、これらのオリゴヌクレオチドは、ペアエンド配列決定プライマーのアニーリングおよびフローセル上の固定化プライマー叢へのハイブリダイゼーションに必要な配列を含有する。 As proof of principle, two capture assays were developed. Initially, 366 OS-Seq primer probes (OS-Seq-366) flanked by 10 oncogene exons were designed (FIG. 3). This assay was intended to test the OS-Seq method and not to test definitive exon coverage. OS-Seq-366 oligonucleotides were synthesized using a column-based method. Next, 11,742 primer probes were designed and synthesized to capture exons of 344 oncogenes to demonstrate extensibility (OS-Seq-11k). These primer probes were tiled over large exons avoiding repeats to improve exon coverage. Oligonucleotides were synthesized on programmable microarrays for high-throughput production of OS-Seq-11k. These array-synthesized oligonucleotides require amplification for processing and to obtain sufficient material for OS-Seq (Figure 4). After processing, the OS-Seq oligonucleotide contains a target specific 40-mer complementary to the 5 ′ end of the target region (FIG. 5). These oligonucleotides contain sequences necessary for hybridization to the immobilized primer flora on annealing and flow cell paired-end sequencing primers.
Claims (17)
a)i)表面結合オリゴヌクレオチドの第1の集団およびii)表面結合オリゴヌクレオチドの第2の集団を含む叢を含む基質を得ることであって、前記表面結合オリゴヌクレオチドの第1および第2の集団のメンバーは基質の表面全体にランダムに分布され、前記基質は空間的にまたは光学的にアドレス指定された単一ヌクレオチドの集団を含まないものであることと、
b)前記表面結合オリゴヌクレオチドの第1の集団の第1のメンバーを、前記第1のメンバーとハイブリダイズする領域およびゲノム配列を含有する領域を含む合成選択オリゴヌクレオチドとハイブリダイズさせることと、
c)前記表面結合オリゴヌクレオチドの第1の集団の前記第1のメンバーを伸長させて、前記ゲノム配列に相補的な配列を含む支持体結合選択プライマーを生成することと、
d)前記支持体結合選択プライマーを、前記ゲノム配列を含む核酸断片を含む断片化されたゲノムとハイブリダイズさせることであって、前記核酸断片が5’末端にアダプターを含むものであることと、
e)前記支持体結合選択プライマーを伸長させて、ゲノム内の前記ゲノム配列に隣接する隣接配列を含有する伸長産物を生成することであって、前記伸長産物が、d)工程のアダプターに相補的な配列を3’末端に含むものであることと、
f)前記表面結合オリゴヌクレオチドの第1および第2の集団の伸長されていないメンバーを使用して、前記基質上で前記伸長産物をブリッジPCRによって増幅して、前記隣接配列を含むPCR産物を生成することであって、前記表面結合オリゴヌクレオチドの第2の集団のメンバーが、e)工程の伸長産物の3’末端のアダプターに相補的な配列とハイブリダイズし、前記隣接配列を含むPCR産物を生成すること
を含む方法。 A method for capturing and amplifying selected sequences comprising:
obtaining a substrate comprising: a) i) a first population of surface-bound oligonucleotides and ii) a plexus comprising a second population of surface-bound oligonucleotides, the first and second of said surface-bound oligonucleotides The members of the population are randomly distributed across the surface of the substrate, the substrate not including a spatially or optically addressed population of single nucleotides ;
b) hybridizing a first member of the first population of said surface bound oligonucleotides with a synthetic selection oligonucleotide comprising a region that hybridizes with said first member and a region containing a genomic sequence;
c) extending the first member of the first population of surface-bound oligonucleotides to generate a support-binding selection primer comprising a sequence complementary to the genomic sequence;
and that the d) the support-bound selection primer, the method comprising fragmenting genomic hybridized comprises a nucleic acid fragment containing the genomic sequence, wherein the nucleic acid fragment is intended to include an adapter at the 5 'end,
e) extending the support-binding selection primer to produce an extension product containing flanking sequences adjacent to the genomic sequence in the genome , wherein the extension product is complementary to the adapter of step d) Including a sequence at the 3 ′ end ,
f) Using the unextended members of the first and second populations of the surface bound oligonucleotides , amplifying the extension product on the substrate by bridge PCR to generate a PCR product comprising the flanking sequences A member of the second population of surface-bound oligonucleotides hybridizes with a sequence complementary to the adapter at the 3 ′ end of the extension product of step e), and a PCR product comprising said flanking sequences Generating .
i.表面結合オリゴヌクレオチドの最初の第2の集団のメンバーを、前記表面結合オリゴヌクレオチドの第2の集団の前記メンバーとハイブリダイズする領域および前記核酸断片の配列に相補的な領域を含むオリゴヌクレオチドとハイブリダイズさせることと、
ii.前記表面結合オリゴヌクレオチドの最初の第2の集団の前記メンバーを伸長させて、前記表面結合オリゴヌクレオチドの第2の集団を生成することと、によって作製される、請求項1に記載の方法。 The second population of surface bound oligonucleotides is:
i. Hybridizing a member of the first second population of surface-bound oligonucleotides with an oligonucleotide comprising a region that hybridizes with the member of the second population of surface-bound oligonucleotides and a region that is complementary to the sequence of the nucleic acid fragment. Making it soy,
ii. The method of claim 1, wherein the method is made by extending the member of the first second population of surface-bound oligonucleotides to generate the second population of surface-bound oligonucleotides.
第2のバーコード配列を含む第2のアダプターを使用して、第2の対象からの断片化されたゲノムDNAにアダプターをライゲートして、第2の産物を生成することと、
前記第1および第2の産物を組み合わせて、混合鋳型を生成することと、
前記混合鋳型を使用して請求項1の方法を行って、各々が前記バーコード配列を含有する第1および第2のPCR産物を提供することと、を含む、請求項12に記載の方法。 Ligating the adapter to fragmented genomic DNA from a first subject using a first adapter comprising a first barcode sequence to produce a first product;
Ligating the adapter to fragmented genomic DNA from a second subject using a second adapter comprising a second barcode sequence to produce a second product;
Combining the first and second products to produce a mixed template;
13. The method of claim 12 , comprising performing the method of claim 1 using the mixed template to provide first and second PCR products, each containing the barcode sequence.
ii.前記アダプターをライゲートした断片を、前記表面結合オリゴヌクレオチドの第1の集団の第1のメンバーとハイブリダイズさせることと、
iii.前記アダプターをライゲートした断片がハイブリダイズされた前記表面結合オリゴヌクレオチドの第1の集団の前記第1のメンバーを伸長させることと、
iv.前記伸長産物の前記アダプターを含有する末端を、第2の支持体結合ポリヌクレオチドとハイブリダイズさせ、それによってブリッジを生成し、ブリッジPCRを促進することと、を含む、請求項1に記載の方法。 i. Ligating the nucleic acid fragment to an adapter containing a site for a sequencing primer and the same nucleotide sequence as the second surface-binding oligonucleotide;
ii. Hybridizing the adapter-ligated fragment with a first member of the first population of surface-bound oligonucleotides;
iii. Elongating the first member of the first population of the surface-bound oligonucleotides to which the adapter-ligated fragment is hybridized;
iv. The method of claim 1, comprising hybridizing the adapter-containing end of the extension product with a second support-binding polynucleotide, thereby generating a bridge and facilitating bridge PCR. .
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